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Lo WK, Fernandez AM, Feldman N, Sharma N, Goldberg HJ, Chan WW. Increased reflux burden on pre-transplant reflux testing independently predicts significant pulmonary function decline after lung transplantation. World J Transplant 2025; 15:100111. [DOI: 10.5500/wjt.v15.i3.100111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 01/08/2025] [Accepted: 02/26/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Gastroesophageal reflux disease has been shown to contribute to allograft injury and rejection outcomes in lung transplantation through a proposed mechanism of aspiration, inflammation, and allograft injury. The value of pre-transplant reflux testing in predicting reduction in pulmonary function after lung transplantation is unclear. We hypothesized that increased reflux burden on pre-transplant reflux testing is associated with pulmonary function decline following lung transplant.
AIM To assess the relationship between pre-transplant measures of reflux and pulmonary function decline in lung transplant recipients.
METHODS This was a retrospective cohort study of lung transplant recipients who underwent pre-transplant reflux testing with 24-hour pH-impedance off acid suppression at a tertiary center in 2007-2016. Patients with pre-transplant fundoplication were excluded. Time-to-event analysis was performed using Cox proportional hazards models to assess associations between reflux measures and reduction in forced expiratory volume in 1 second (FEV1) of ≥ 20% post-transplant. Patients not meeting endpoint were censored at time of post-transplant fundoplication, last clinic visit, or death, whichever was earliest.
RESULTS Seventy subjects (58% men, mean age: 56 years) met the inclusion criteria. Interstitial lung disease represented the predominant pulmonary diagnosis (40%). Baseline demographics were similar between groups and were not associated with pulmonary decline. The clinical endpoint (≥ 20% FEV1 decline) was reached in 18 subjects (26%). In time-to-event univariate analysis, FEV1 decline was associated with increased acid exposure time (AET) [hazard ratio (HR) = 3.49, P = 0.03] and increased proximal acid reflux (HR = 3.34, P = 0.04) with confirmation on Kaplan-Meier analysis. Multivariate analysis showed persistent association between pulmonary decline and increased AET (HR = 3.37, P = 0.04) when controlling for potential confounders including age, body mass index, and sex. Sub-group analysis including only patients with FEV1 decline showed that all subjects with abnormal AET progressed to bronchiolitis obliterans syndrome.
CONCLUSION Increased reflux burden on pre-transplant testing was associated with significant pulmonary function decline post-transplant. Pre-transplant reflux assessment may provide clinically relevant information in the prognostication and management of transplant recipients.
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Affiliation(s)
- Wai-Kit Lo
- Department of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women’s Hospital, Boston, MA 02115, United States
| | - Annel M Fernandez
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, United States
| | - Natan Feldman
- Department of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women’s Hospital, Boston, MA 02115, United States
| | - Nirmal Sharma
- Department of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women’s Hospital, Boston, MA 02115, United States
| | - Hilary J Goldberg
- Department of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA 02115, United States
| | - Walter W Chan
- Department of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women’s Hospital, Boston, MA 02115, United States
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Lo WK, Muftah M, Goldberg HJ, Sharma N, Chan WW. Concurrent abnormal non-acid reflux is associated with additional chronic rejection risk in lung transplant patients with increased acid exposure. Dis Esophagus 2024; 37:doae020. [PMID: 38521967 PMCID: PMC11466852 DOI: 10.1093/dote/doae020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 03/04/2024] [Indexed: 03/25/2024]
Abstract
Acid reflux has been associated with allograft injury and rejection in lung transplant patients; however, the pathogenic role of non-acid reflux remains debated. We aimed to evaluate the impact of concurrent abnormal non-acid reflux with acid reflux on chronic rejection in lung transplant patients with acid reflux. This was a retrospective cohort study of lung transplant recipients who underwent pre-transplant combined impedance-pH study off acid suppression. Only subjects with acid exposure >4% were included. Non-acid reflux (pH > 4) episodes >27 was considered abnormal per prior normative studies. Chronic rejection was defined as chronic lung allograft dysfunction (CLAD) per International Society for Heart and Lung Transplantation criteria. Time-to-event analyses were performed using Cox proportional hazards and Kaplan-Maier methods, with censoring at death, anti-reflux surgery, or last follow-up. In total, 68 subjects (28 abnormal/40 normal non-acid reflux) met inclusion criteria for the study. Baseline demographic/clinical characteristics were similar between groups. Among this cohort of patients with increased acid exposure, subjects with concurrent abnormal non-acid reflux had significantly higher risk of CLAD than those without on Kaplan-Meier analysis (log-ranked P = 0.0269). On Cox multivariable regression analysis controlling for body mass index, age at transplantation, and proton pump inhibitor use, concurrent abnormal non-acid reflux remained independently predictive of increased CLAD risk (hazard ratio 2.31, confidence interval: 1.03-5.19, P = 0.04). Presence of concurrent abnormal non-acid reflux in lung transplant subjects with increased acid exposure is associated with additional risk of chronic rejection. Non-acid reflux may also contribute to pathogenicity in lung allograft injury/rejection, supporting a potential role for impedance-based testing in this population.
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Affiliation(s)
- Wai-Kit Lo
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Boston, MA, USA
- Division of Gastroenterology, Boston VA Healthcare System, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Mayssan Muftah
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Hilary J Goldberg
- Harvard Medical School, Boston, MA, USA
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA
| | - Nirmal Sharma
- Harvard Medical School, Boston, MA, USA
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA
| | - Walter W Chan
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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Yang NY, Parish A, Posner S, Shimpi RA, Wood RK, Finn RT, Fisher DA, Hartwig MG, Klapper JA, Reynolds J, Niedzwiecki D, Leiman DA. Acid exposure time is sensitive for detecting gastroesophageal reflux disease and is associated with long-term survival after lung transplant. Dis Esophagus 2023; 36:doac114. [PMID: 36572397 DOI: 10.1093/dote/doac114] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/27/2022] [Accepted: 12/04/2022] [Indexed: 07/28/2023]
Abstract
Gastroesophageal reflux disease (GERD) is common in patients who have undergone lung transplantation and is associated with poorer outcomes, but guidelines are lacking to direct management strategies in this population. We assessed the diagnostic yield of impedance metrics compared to pH-metry alone for detecting GERD among lung transplant recipients and evaluated their association with clinical outcomes. We performed a retrospective cohort study of consecutive patients who underwent lung transplantation. Demographic data, acid exposure time (AET), number of reflux episodes, mean nocturnal baseline impedance (MNBI), post-reflux swallowing-induced peristaltic wave index (PSPWI), and clinical outcomes including mortality were collected. The relationship between GERD metrics and clinical outcomes was assessed using Wilcoxon signed-rank test and Fisher's exact test as appropriate. Of the 76 patients studied, 29 (38%) had GERD based on abnormal AET after lung transplantation. One (1.3%) patient had GERD based on elevated number of reflux episodes and abnormal distal MNBI detected GERD in 19 (26%) patients, resulting in 62% sensitivity and 94% specificity. Two (2.6%) patients had normal PSPWI. Patients with low distal MNBI had significantly decreased forced expiratory volume in 1 second (FEV1) at 3-year posttransplant compared to those without low distal MNBI (P = 0.03). Three-year survival was significantly worse among patients with elevated AET (66.7% vs. 89.1%, P = 0.03) but not with low distal MNBI (68.4% vs. 84.3%, P = 0.18). Abnormal AET is more sensitive for detecting GERD than other reflux metrics studied and is associated with survival, suggesting pH-metry alone may be sufficient to guide GERD management after lung transplant.
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Affiliation(s)
- Nancy Y Yang
- Division of Gastroenterology, Duke University, Durham, NC, USA
| | - Alice Parish
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
| | - Shai Posner
- Albany Gastroenterology Consultants, Albany, NY, USA
| | - Rahul A Shimpi
- Division of Gastroenterology, Duke University, Durham, NC, USA
| | - Richard K Wood
- Division of Gastroenterology, Duke University, Durham, NC, USA
| | - R Thomas Finn
- Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | | | - Matthew G Hartwig
- Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC, USA
| | - Jacob A Klapper
- Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC, USA
| | - John Reynolds
- Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center, Durham, NC, USA
| | - Donna Niedzwiecki
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
| | - David A Leiman
- Division of Gastroenterology, Duke University, Durham, NC, USA
- Duke Clinical Research Institute, Durham, NC, USA
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Lo WK, Flanagan R, Sharma N, Goldberg HJ, Chan WW. Pre-Lung transplant reflux testing demonstrates high prevalence of gastroesophageal reflux in cystic fibrosis and reduces chronic rejection risk. World J Transplant 2023; 13:138-146. [PMID: 37388387 PMCID: PMC10303416 DOI: 10.5500/wjt.v13.i4.138] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 03/22/2023] [Accepted: 03/31/2023] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND Gastroesophageal reflux (GER) has been associated with poor outcomes after lung transplantation for chronic lung disease, including increased risk of chronic rejection. GER is common in cystic fibrosis (CF), but factors influencing the likelihood of pre-transplant pH testing, and the impact of testing on clinical management and transplant outcomes in patients with CF are unknown. AIM To evaluate the role of pre-transplant reflux testing in the evaluation of lung transplant candidates with CF. METHODS This was a retrospective study from 2007-2019 at a tertiary medical center that included all patients with CF undergoing lung transplant. Patients with pre-transplant anti-reflux surgery were excluded. Baseline characteristics (age at transplantation, gender, race, body mass index), self-reported GER symptoms prior to transplantation, and pre-transplant cardiopulmonary testing results, were recorded. Reflux testing consisted of either 24-h pH- or combined multichannel intraluminal impedance and pH monitoring. Post-transplant care included a standard immunosuppressive regimen, and regular surveillance bronchoscopy and pulmonary spirometry in accordance with institutional practice as well as in symptomatic patients. The primary outcome of chronic lung allograft dysfunction (CLAD) was defined clinically and histologically per International Society of Heart and Lung Transplantation criteria. Statistical analysis was performed with Fisher's exact test to assess differences between cohorts, and time-to-event Cox proportional hazards modeling. RESULTS After applying inclusion and exclusion criteria, a total of 60 patients were included in the study. Among all CF patients, 41 (68.3%) completed reflux monitoring as part of pre-lung transplant evaluation. Objective evidence of pathologic reflux, defined as acid exposure time > 4%, was found in 24 subjects, representing 58% of the tested group. CF patients with pre-transplant reflux testing were older (35.8 vs 30.1 years, P = 0.01) and more commonly reported typical esophageal reflux symptoms (53.7% vs 26.3%, P = 0.06) compared to those without reflux testing. Other patient demographics and baseline cardiopulmonary function did not significantly differ between CF subjects with and without pre-transplant reflux testing. Patients with CF were less likely to undergo pre-transplant reflux testing compared to other pulmonary diagnoses (68% vs 85%, P = 0.003). There was a decreased risk of CLAD in patients with CF who underwent reflux testing compared to those who did not, after controlling for confounders (Cox Hazard Ratio 0.26; 95%CI: 0.08-0.92). CONCLUSION Pre-transplant reflux testing revealed high prevalence of pathologic reflux in CF patients and was associated with decreased risk of CLAD. Systematic reflux testing may enhance outcomes in this patient population.
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Affiliation(s)
- Wai-Kit Lo
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Ryan Flanagan
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Nirmal Sharma
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Hilary J Goldberg
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Walter W Chan
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
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Lo WK, Hiramoto B, Goldberg HJ, Sharma N, Chan WW. Ineffective esophageal motility is associated with acute rejection after lung transplantation independent of gastroesophageal reflux. World J Gastroenterol 2023; 29:3292-3301. [PMID: 37377592 PMCID: PMC10292138 DOI: 10.3748/wjg.v29.i21.3292] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/14/2023] [Accepted: 04/28/2023] [Indexed: 06/01/2023] Open
Abstract
BACKGROUND Gastroesophageal reflux is associated with poorer outcomes after lung transplant, likely through recurrent aspiration and allograft injury. Although prior studies have demonstrated a relationship between impedance-pH results and transplant outcomes, the role of esophageal manometry in the assessment of lung transplant patients remains debated, and the impact of esophageal dysmotility on transplant outcomes is unclear. Of particular interest is ineffective esophageal motility (IEM) and its associated impact on esophageal clearance.
AIM To assess the relationship between pre-transplant IEM diagnosis and acute rejection after lung transplantation.
METHODS This was a retrospective cohort study of lung transplant recipients at a tertiary care center between 2007 and 2018. Patients with pre-transplant anti-reflux surgery were excluded. Manometric and reflux diagnoses were recorded from pre-transplant esophageal function testing. Time-to-event analysis using Cox proportional hazards model was applied to evaluate outcome of first episode of acute cellular rejection, defined histologically per International Society of Heart and Lung Transplantation guidelines. Subjects not meeting this endpoint were censored at time of post-transplant anti-reflux surgery, last clinic visit, or death. Fisher’s exact test for binary variables and student’s t-test for continuous variables were performed to assess for differences between groups.
RESULTS Of 184 subjects (54% men, mean age: 58, follow-up: 443 person-years) met criteria for inclusion. Interstitial pulmonary fibrosis represented the predominant pulmonary diagnosis (41%). During the follow-up period, 60 subjects (33.5%) developed acute rejection. The all-cause mortality was 16.3%. Time-to-event univariate analyses demonstrated significant association between IEM and acute rejection [hazard ratio (HR): 1.984, 95%CI: 1.03-3.30, P = 0.04], confirmed on Kaplan-Meier curve. On multivariable analysis, IEM remained independently associated with acute rejection, even after controlling for potential confounders such as the presence of acid and nonacid reflux (HR: 2.20, 95%CI: 1.18-4.11, P = 0.01). Nonacid reflux was also independently associated with acute rejection on both univariate (HR: 2.16, 95%CI: 1.26-3.72, P = 0.005) and multivariable analyses (HR: 2.10, 95%CI: 1.21-3.64, P = 0.009), adjusting for the presence of IEM.
CONCLUSION Pre-transplant IEM was associated with acute rejection after transplantation, even after controlling for acid and nonacid reflux. Esophageal motility testing may be considered in lung transplant to predict outcomes.
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Affiliation(s)
- Wai-Kit Lo
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA 02115, United States
| | - Brent Hiramoto
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA 02115, United States
| | - Hilary J Goldberg
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, United States
| | - Nirmal Sharma
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, United States
| | - Walter W Chan
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA 02115, United States
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Zhou JC, Gavini S, Chan WW, Lo WK. Relationship Between Esophageal Disease and Pulmonary Fibrosis. Dig Dis Sci 2023; 68:1096-1105. [PMID: 36918450 DOI: 10.1007/s10620-023-07908-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/27/2023] [Indexed: 03/16/2023]
Abstract
Esophageal disorders are prevalent among patients with chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). Gastroesophageal reflux disease (GERD) has been associated with IPF prevalence, severity, and respiratory decline. The pathophysiologic relationship between GERD and IPF is likely bidirectional, with aspiration of refluxate leading to lung inflammation and fibrosis, while the restrictive pulmonary physiology may contribute to altered transdiaphragmatic pressure gradient and increased reflux. Esophageal symptoms are frequently absent and do not predict esophageal dysfunction or pathologic reflux in patients with IPF, and objective diagnostic tools including upper endoscopy, ambulatory reflux monitoring, and high-resolution manometry are often needed. Impedance-based testing that identifies both weakly/non-acidic and acid reflux may provide important additional diagnostic value beyond pH-based acid testing alone. Novel metrics and maneuvers, including advanced impedance measures on impedance-pH study and provocative testing on HRM, may hold promise to future diagnostic advancements. The main treatment options include medical therapy with acid suppressants and anti-reflux surgery, although their potential benefits in pulmonary outcomes of IPF require further validations. Future directions of research include identifying phenotypes of IPF patients who may benefit from esophageal testing and treatment, determining the optimal testing strategy and protocol, and prospectively assessing the value of different esophageal therapies to improve outcomes while minimizing risks. This review will discuss the pathophysiology, evaluation, and management of esophageal diseases, particularly GERD, in patients with IPF, as informed by the most recent publications in the field, in hopes of identifying targets for future study and research.
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Affiliation(s)
- Joyce C Zhou
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Sravanya Gavini
- Division of Digestive and Liver Diseases, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Walter W Chan
- Harvard Medical School, Boston, MA, USA.
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.
| | - Wai-Kit Lo
- Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA
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Routine Reflux Testing Guides Timely Antireflux Treatment to Reduce Acute and Chronic Rejection After Lung Transplantation. Clin Transl Gastroenterol 2022; 14:e00538. [PMID: 36201668 PMCID: PMC9875950 DOI: 10.14309/ctg.0000000000000538] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 09/23/2022] [Indexed: 01/31/2023] Open
Abstract
INTRODUCTION Gastroesophageal reflux has been associated with poorer lung transplantation outcomes, although no standard approach to evaluation/management has been adopted. We aimed to evaluate the effect of timely antireflux treatment as guided by routine reflux testing on postlung transplant rejection outcomes. METHODS This was a retrospective cohort study of lung transplant recipients at a tertiary center. All patients underwent pretransplant ambulatory pH monitoring. Timely antireflux treatment was defined as proton pump inhibitor initiation or antireflux surgery within 6 months of transplantation. Patients were separated into 3 groups: normal pH monitoring (-pH), increased reflux (+pH) with timely treatment, and +pH with delayed treatment. Rejection outcomes included acute rejection, bronchiolitis obliterans syndrome, and chronic lung allograft dysfunction per International Society for Heart and Lung Transplantation criteria. Time-to-event analyses using Cox proportional hazard models were applied. Patients not meeting outcomes were censored at death or last clinic visit. RESULTS One hundred seventy-five patients (59% men/mean 56.3 yr/follow-up: 496 person-years) were included. On multivariable analyses, +pH/delayed treatment patients had higher risks of acute rejection (adjust hazard ratio [aHR]:3.81 [95% confidence interval [CI]: 1.90-7.64], P = 0.0002), bronchiolitis obliterans syndrome (aHR: 2.22 [95% CI: 1.07-4.58], P = 0.03), and chronic lung allograft dysfunction (aHR: 2.97 [95% CI: 1.40-6.32], P = 0.005) than +pH/timely treatment patients. Similarly, rejection risks were increased among +pH/delayed treatment patients vs -pH patients (all P < 0.05). No significant differences in rejection risks were noted between +pH/timely treatment patients and -pH patients. Failure/complications of antireflux treatment were rare and similar among groups. DISCUSSION Timely antireflux treatment, as directed by pretransplant reflux testing, was associated with reduced allograft rejection risks and demonstrated noninferiority to patients without reflux. A standardized peri-transplant test-and-treat algorithm may guide timely reflux management to improve lung transplant outcomes.
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Abstract
The aim of this review is to explore the relationship between esophageal syndromes and pulmonary diseases considering the most recent data available. Prior studies have shown a close relationship between lung diseases such as asthma, chronic obstructive pulmonary disorders (COPD), Idiopathic pulmonary fibrosis (IPF), and lung transplant rejection and esophageal dysfunction. Although the association has long been demonstrated, the exact relationship remains unclear. Clinical experience has shown a bidirectional relationship where esophageal disease may influence the outcomes of pulmonary disease and vice versa. The impact of esophageal dysfunction on pulmonary disorders may also be related to 2 different mechanisms: the reflux pathway leading to microaspiration and the reflex pathway triggering vagally mediated airway reactions. The aim of this review is to further explore these relationships and pathophysiologic mechanisms. Specifically, we discuss the proposed hypotheses for the relationship between the 2 diseases, as well as the pathophysiology and new developments in clinical management.
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Davidson JR, Franklin D, Kumar S, Mohammadi B, Dawas K, Eaton S, Curry J, De Coppi P, Abbassi-Ghadi N. Fundoplication to preserve allograft function after lung transplant: Systematic review and meta-analysis. J Thorac Cardiovasc Surg 2020; 160:858-866. [DOI: 10.1016/j.jtcvs.2019.10.185] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 10/08/2019] [Accepted: 10/25/2019] [Indexed: 12/29/2022]
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Chan WW, Ahuja N, Fisichella PM, Gavini S, Rangan V, Vela MF. Extraesophageal syndrome of gastroesophageal reflux: relationships with lung disease and transplantation outcome. Ann N Y Acad Sci 2020; 1482:95-105. [PMID: 32808313 DOI: 10.1111/nyas.14460] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/05/2020] [Accepted: 07/15/2020] [Indexed: 12/14/2022]
Abstract
Gastroesophageal reflux disease (GERD) is prevalent and may be associated with both esophageal and extraesophageal syndromes, which include various pulmonary conditions. GERD may lead to pulmonary complications through the "reflux" (aspiration) or "reflex" (refluxate-triggered, vagally mediated airway spasm) mechanisms. While GERD may cause or worsen pulmonary disorders, changes in respiratory mechanics due to lung disease may also increase reflux. Typical esophageal symptoms are frequently absent and objective assessment with reflux monitoring is often needed for diagnosis. Impedance monitoring should be considered in addition to traditional pH study due to the involvement of both acidic and weakly acidic/nonacidic reflux. Antireflux therapy may improve outcomes of some pulmonary complications of GERD, although careful selection of a candidate is paramount to successful outcomes. Further research is needed to identify the optimal testing strategy and patient phenotypes that would benefit from antireflux therapy to improve pulmonary outcomes.
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Affiliation(s)
- Walter W Chan
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Nitin Ahuja
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - P Marco Fisichella
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Sravanya Gavini
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Vikram Rangan
- Division of Gastroenterology, Hepatology, and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Marcelo F Vela
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona
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Increased Acid Exposure on Pretransplant Impedance-pH Testing Is Associated With Chronic Rejection After Lung Transplantation. J Clin Gastroenterol 2020; 54:517-521. [PMID: 32091450 DOI: 10.1097/mcg.0000000000001331] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
GOAL The goal of this study was to assess the relationship between pretransplant measures of reflux and longer-term outcomes of chronic allograft rejection in lung transplant recipients. BACKGROUND Bronchiolitis obliterans syndrome (BOS) is a primary measure of morbidity and mortality following lung transplantation, and a manifestation of chronic lung allograft dysfunction (CLAD). Acid reflux has been associated with early allograft injury through a proposed mechanism of aspiration and activation of the inflammatory cascade, but its association with chronic rejection is unclear. STUDY This was a retrospective cohort study of lung transplant recipients undergoing impedance-pH testing off proton pump inhibitor from 2007 to 2016. Patients with pretransplant antireflux surgery were excluded. Time-to-event analysis using the Cox proportional hazards model was applied to assess the relationship between pretransplant reflux measures and the development of BOS, defined histologically and clinically. A secondary analysis was completed using CLAD as the outcome variable. RESULTS Fifty-one subjects (59% men, mean age: 56, mean follow-up: 2.2 y) met inclusion criteria for the study. The BOS endpoint was reached in 13 subjects (28%). In time-to-event analyses, BOS was associated with increased acid exposure, defined as >4.2% of time with pH<4 [hazard ratio (HR): 4.18; 95% confidence interval (CI): 1.31-13.4; P=0.01], and elevated DeMeester score >14.7 (HR: 3.08; 95% CI: 1.02-9.26; P=0.04), with confirmation from Kaplan-Meier analyses. The secondary analysis demonstrated a similar association between increased acid exposure and CLAD (HR: 3.28; 95% CI: 1.09-9.88; P=0.03), which persisted on multivariate models. CONCLUSION Increased acid exposure on pretransplant reflux testing was associated with the development of BOS and CLAD, both measures of chronic allograft rejection, after lung transplantation, and may provide clinically relevant information to improve lung allograft survival through aggressive reflux management.
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12
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Ghisa M, Marinelli C, Savarino V, Savarino E. Idiopathic pulmonary fibrosis and GERD: links and risks. Ther Clin Risk Manag 2019; 15:1081-1093. [PMID: 31564886 PMCID: PMC6733342 DOI: 10.2147/tcrm.s184291] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 08/11/2019] [Indexed: 01/06/2023] Open
Abstract
Gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) are two pathological conditions often strictly related, even if a clear relationship of causality has not been demonstrated. GERD is a frequent comorbidity in IPF patients, as demonstrated using combined multichannel intraluminal impedance-pH, despite being mostly clinically silent. According to that, it has been hypothesized that microaspiration of gastric material may play a fundamental role in the fibrotic transformation of pulmonary parenchyma. In contrast, it cannot be excluded that IPF may favor GERD by increasing the negative intrathoracic pressure. Therefore, this relationship is uncertain as well as not univocal. Nevertheless, the latest international guidelines recommend the use of proton pump inhibitors (PPIs) in IPF based on several data showing that PPIs can stabilize lung function, reduce disease flares and hospitalizations. On the contrary, recent studies not only question the relevance of these results, but also associate the use of PPIs with an increased risk of lung infections and a negative prognostic outcome. The aim of this review is to analyze the possible links between GERD and IPF and their possible therapeutic implications, trying to translate this scientific evidence into useful information for clinical practice.
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Affiliation(s)
- Matteo Ghisa
- Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Carla Marinelli
- Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Vincenzo Savarino
- Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Edoardo Savarino
- Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
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Causes, Preventability, and Cost of Unplanned Rehospitalizations Within 30 Days of Discharge After Lung Transplantation. Transplantation 2019; 102:838-844. [PMID: 29346256 DOI: 10.1097/tp.0000000000002101] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Unplanned rehospitalizations (UR) within 30 days of discharge are common after lung transplantation. It is unknown whether UR represents preventable gaps in care or necessary interventions for complex patients. The objective of this study was to assess the incidence, causes, risk factors, and preventability of UR after initial discharge after lung transplantation. METHODS This was a single-center prospective cohort study. Subjects completed a modified short physical performance battery to assess frailty at listing and at initial hospital discharge after transplantation and the State-Trait Anxiety Inventory at discharge. For each UR, a study staff member and the patient's admitting or attending clinician used an ordinal scale (0, not; 1, possibly; 2, definitely preventable) to rate readmission preventability. A total sum score of 2 or higher defined a preventable UR. RESULTS Of the 90 enrolled patients, 30 (33.3%) had an UR. The single most common reasons were infection (7 [23.3%]) and atrial tachyarrhythmia (5 [16.7%]). Among the 30 URs, 9 (30.0%) were deemed preventable. Unplanned rehospitalization that happened before day 30 were more likely to be considered preventable than those between days 30 and 90 (30.0% versus 6.2%, P = 0.04). Discharge frailty, defined as short physical performance battery less than 6, was the only variable associated with UR on multivariable analysis (odds ratio, 3.4; 95% confidence interval, 1.1-11.8; P = 0.04). CONCLUSIONS Although clinicians do not rate the majority of UR after lung transplant as preventable, discharge frailty is associated with UR. Further research should identify whether modification of discharge frailty can reduce UR.
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Lo WK, Goldberg HJ, Wee J, Fisichella PM, Chan WW. Both Pre-Transplant and Early Post-Transplant Antireflux Surgery Prevent Development of Early Allograft Injury After Lung Transplantation. J Gastrointest Surg 2016; 20:111-8; discussion 118. [PMID: 26493975 DOI: 10.1007/s11605-015-2983-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 10/10/2015] [Indexed: 01/31/2023]
Abstract
BACKGROUND Antireflux surgery (ARS) has been associated with improved lung transplant outcomes. Pre-transplant ARS has been shown in small studies to improve pulmonary function among transplant candidates with gastroesophageal reflux disease (GERD). Although early post-transplant ARS has been shown to be effective in reducing chronic rejection, the optimal timing of ARS in transplant recipients remains unclear. The aim of this study is to evaluate the time to early allograft injury among lung transplant recipients by timing of ARS. METHODS This was a retrospective cohort study of lung transplant recipients undergoing ARS before or after transplantation at a tertiary care center since 2007, with at least 1-year follow-up. Early allograft injury was defined clinically and histologically as acute rejection or lymphocytic bronchiolitis, occurring within the first year after transplantation. In accordance with prior studies, the cutoff between early and late post-transplant ARS was set at 6 months. Time-to-event analysis using the Cox proportional hazards model was applied to assess the relationship between timing of surgery and early allograft injury. Subjects not meeting this outcome were censored at 1 year in the time-to-event analysis. Fisher’s exact test for binary variables and Student’s t test for continuous variables were performed to assess for differences among the three groups: ARS pre-transplant, ARS early post-transplant, and ARS late post-transplant. RESULTS Forty-eight subjects (60% men, mean age 55) met the inclusion criteria for the study. Patient demographics, pre-transplant cardiopulmonary function, BMI, CMV status, and PPI exposure were similar between groups. Kaplan-Meier analysis demonstrated significantly increased early allograft injury in late post-transplant ARS patients compared with both pre-transplant (log-rank p = 0.007) and early post-transplant (log-rank p = 0.05) patients, as well as a significant trend across groups (log-rank p = 0.005). No significant difference between pre- and early post-transplant groups was noted. Three ARS failures were noted in the pre- and late post-transplant groups. Complications included one death due to aspiration pneumonia in a late post-transplant ARS recipient. No early post-transplant ARS patients experienced ARS failure or complications. CONCLUSION Late post-lung transplant ARS resulted in increased risk of early allograft injury compared to pre-transplant and early post-transplant ARS. Both pre- and early post-transplant ARS appear equally safe and effective in improving lung transplant outcomes. These findings support consideration of aggressive reflux testing and application of antireflux measures before or soon after transplantation to minimize the impact of reflux on allograft injury.
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